We have found that HIV-1 transgenic rats and HIV-1-treated co-cultures containing human pulmonary artery endothelial cells (HPAEC) and peripheral blood mononuclear cells (PBMC) demonstrate striking increases in arachidonate 5-lipoxygenase (AL0X5) mRNA expression. AL0X5 is the enzyme that produces leukotrienes (LT) from arachidonic acid. These LT include LTB4 and the potent vasoconstrictors, LTC4, LTD4 and LTE4. We believe HIV-induced increases in AL0X5 expression could yield elevated LT levels and potentially contribute to the progression of PAH, a disorder characterized by pulmonary vasoconstriction and vascular remodeling, by inducing vasoconstriction of the pulmonary vasculature. Previous works suggest that HIV-1 may play a role in PAH pathogenesis through the release of various virus-associated mediators and not through direct vascular contact. One potential mechanism in the etiology of HIV-associated PAH may exist in the effect of HlV-1 secreted proteins, such as Tat, Nef or gp120. Numerous works have described the effect of HIV-1 protein exposure on human endothelial cells showing increased gene and protein expression of various vasoactive molecules. These studies suggest an active link between HIV-1 proteins and the development of disorders affecting the vasculature. Therefore, we hypothesize that the HIV-1 protein(s) may contribute to HIV-PAH development by altering AL0X5 expression and leukotriene production. To test this hypothesis, we will employ cell cultures and a HIV-1 transgenic (Tg) rat model. Human pulmonary artery endothelial cells will be cultured in the presence or absence of HlV-1 proteins for various exposure times. AL0X5 transcription will be assessed by real-fime PCR and nuclear run-on assays. AL0X5 protein expression and leukotriene producfion will be assessed by western blot and ELISA, respectively. We will also investigate the role of AL0X5 in HIV-PAH progression by administering the AL0X5 inhibitor, Zileuton to HlV-1 Tg rats in the presence or absence of hypoxia. Therefore, in this study, we aim to 1) determine the HIV-1 protein(s) that mediate alterations in endothelial AL0X5 expression and activity and 2) assess the role of AL0X5 in HIV-related PAH. These analyses will lead to a better understanding of HIV-PAH and may yield future preventative measures and therapies for HIV-PAH and PAH sufferers. Moreover, these studies may elucidate ALOX5 expression as a potential biomarker of HIV-PAH disease development and severity. PUBLIC HEALTH RELEVANCE: As a fellowship recipient, I aim to participate in publication, proposal and grant-writing workshops. The ability to write clearly and concisely plays a critical role in academia and is an essential tool in becoming a successful scientific investigator. I also plan to participate in a variety of teaching opportunities. As an aspiring college professor, it is incredibly vital to be skilled at conveying information to others in an engaging manner In addition this fellowship will prove especially helpful in the completion of my dissertation and transition to an academic faculty member. The last two years will coincide with the senior segment of my graduate education. At this stage, it will become imperative that I utilize the available mentorships to assist me in obtaining postdoctoral appointments. Following the completion of my doctoral degree, I plan to obtain a postdoctoral position in a prominent laboratory studying pulmonary vascular disease. During this time, I plan to acquire further research training and experience teaching at the collegiate level. Attaining a professoriate position at a minority-serving institution is a long-term goal and personal career objective. It is very important that well-qualified and passionate teachers and professors remain a staple in today's schools and universities. These academic faculty members play a critical role in inspiring our youth to become the next generation of teachers, scientists, and doctors.